Bosentan, represented by structural formula (I) and chemically named 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide, is an endothelin receptor antagonist. It is useful for the treatment of cardiovascular disorders such as hypertension, ischemia, vasospasm and angina pectoris. Bosentan is currently marketed as Tracleer® and indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with grade III functional status.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Each crystalline structure is termed a polymorph and may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms (or crystalline structures) where each form can have different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. The solubility and, consequently, rates of uptake in the body may vary accordingly, leading to lower or higher biological activity than desired. In extreme cases an undesired polymorph can even show toxicity (see, for example, K. Knapman, Modern Drug Discoveries, March 2000, page 53). The occurrence of an unknown polymorphic form during manufacture can have an enormous impact. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry, Differential Scanning calorimetry, Thermo-Gravimetric Analysis and melting point analysis. Additionally, the properties of different polymorphic forms of the same active pharmaceutical ingredient are well known in the pharmaceutical art to have an effect on the manufacture of drug product compositions comprising the API. For example, the solubility, stability, flowability, tractability and compressibility of the API as well as the safety and efficacy of the drug product can be dependent on the polymorphic form.
Understanding and controlling polymorphism, then, gives a decided advantage in bringing new drugs to the marketplace. First, predicting any possible polymorphs for a drug product can be used to diminish the possibility of contamination during a drug's manufacture or storage by other polymorphic forms. Failure to catch contamination can have life-threatening consequences in some cases. Crystallizing an unintended polymorph during manufacture can mean weeks or even months of production downtime, while scientists find and correct the cause of the new crystal form or go through another round of testing to obtain approval for the new form.
So critical are the potential effects of different polymorphic forms in a single drug substance on the safety and efficacy of the respective drug product(s) that the United States Food and Drug Administration (FDA) requires each drug substance manufacturer, at least to control its synthetic processes such that the percentages of the various respective polymorphic forms, when present, must be controlled and consistent among batches and within the drug substance/product's specification as approved by the FDA. Left uncontrolled in synthetic processes, the percentage of a given polymorph outside of an FDA approved specification could render the adulterated batches unfit for commercial sale. Accordingly, the FDA typically requires full characterization of each drug substance used in each drug product marketed in the United States, including the identification and control of polymorphic forms. The FDA further requires robust synthetic process specifications and controls which consistently produce the respective drug substance and drug product.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Preparation of novel polymorphic forms can also provide products having high chemical and polymorphic purity, i.e. with low levels of chemical impurities or other crystalline forms respectively. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.